There are various production methods of 2,6-dihalopurine of the formula
wherein X1 and X2 are the same or different and each is halogen atom. Known methods include, for example, (A) a method comprising chlorination of xanthine with pyrophosphoryl chloride (Journal of American Chemical Society, 78, 3508-10 (1956)), (B) a method comprising chlorination of N-oxide of hipoxanthine or 6-chloropurine with phosphorus oxychloride (JP-B-45-11508, U.S. Pat. No. 3,314,938), (C) a production method comprising 4 steps using barbituric acid derivative as a starting material (Journal of Organic Chemistry, 19, 930 (1954), Journal of American Chemical Society, 80, 404-8 (1958)), (D) a production method comprising cyclization of 2,4-dichloro-5,6-diaminopyrimidine (U.S. Pat. No. 2,844,576) and the like.
However, the aforementioned method (A) is associated with defects in that it requires preparation of pyrophosphoryl chloride as a chlorinating agent from phosphorus oxychloride by a complicated method, as well as a high reaction temperature of 165° C., the use of a corrosion resistant reaction container for the reaction and a long reaction time of about 19 hours. The aforementioned methods (A)-(D) are all defective in that they require long steps and complicated manipulations.
In addition, use of a method using a starting material, wherein the 9-position of the purine ring is alkylated, has been considered, and the following reaction was reported in, for example, J. Chem. Soc., Perkin Trans. 1, 1999, 3469-3475
In this reaction, chlorotrimethylsilane and isoamyl nitrite were used in dichloromethane to give dichloropurine derivative, wherein the 9-position of the purine ring was alkylated, in a yield of 61%.
Furthermore, J. Chem. Soc., Perkin Trans. 1, 1989, 2207-2213 reports the following reaction
In this reaction, isoamyl nitrite was used in carbon tetrachloride to give dichloropurine derivative, wherein the 9-position of the purine ring was alkylated, in a low yield of 40%. To obtain the objective 2,6-dihalopurine, wherein the 9-position is unsubstituted, the alkyl group at the 9-position needs to be removed. However, there is no known method for this end, and conversion to 2,6-dihalopurine, wherein the 9-position is unsubstituted, is difficult. Thus, this method is not a preferable one.
In view of the above, the development of a convenient production method to afford the objective 2,6-dihalopurine in a high yield is desired, which allows easy isolation thereof.
It is therefore an object of the present invention to provide a method for conveniently producing the objective 2,6-dihalopurine in a high yield, which allows easy isolation thereof.